Antigen processing and presentation

Peptide binding to HLA class I and II proteins plays an important role in the function of these molecules. The way in which peptides are derived and the binding procedure differs for the two classes of molecules, and this is reflected in the different function of these molecules.

HLA class I molecules are assembled within the endoplasmic reticulum (ER). The heavy chain is directed to the ER via a leader peptide sequence. Within the lumen of the ER, the extracellular domains of the heavy chain associate with P2-microglobulin. This association is mediated by ER-resident chaperones including calnexin and calreticulum.

Association with peptide also occurs within the ER. Peptides are derived from the cytoplasmic degradation of molecules that takes place in the proteasome, a multicatalytic protein complex. Peptides produced by the proteasome are actively transported into the ER via a transmembrane peptide pump called TAP (transporter associated with antigen processing). Association between HLA class I heavy chain-P2-microglobulin complex and peptide is catalysed by another ER resident chaperone called tapasin.

Once the class I trimolecular complex is formed, the molecule can leave the ER and complete its journey to the cell surface via the Golgi apparatus.

molecule. Both a- and ß-chains are directed to the ER, where a complex of three aß chains and three invariant chains is formed. The invariant chain (Ii) is also a transmembrane protein. Association of HLA class II molecules with Ii effectively blocks the peptide binding site on the class II molecule, thus preventing association of ER-resident peptides. Invariant chain cytoplasmic tail sequences direct the class II molecule through the Golgi apparatus, but, unlike class I molecules, the class II molecules make a detour to endosomal vesicles before arriving at the cell surface. The non-classical HLA-DM and HLA-DO molecules are located within endosomal vesicles, and it is here that the Ii chain is cleaved, leaving a peptide, called CLIP, to block the class II peptide binding cleft. Specific peptide binding is catalysed by HLA-DM, and may also be aided by HLA-DO. The peptides that bind to class II molecules are derived either from internalization of cell surface or from extracellular proteins. Thus, the antigen presentation pathway for HLA class II molecules differs from that of HLA class I molecules by directing the class II molecules to a location where they can bind peptides that differ from those presented by class I molecules.

Once presented at the cell surface, HLA molecules are subjected to surveillance by circulating T cells and natural killer (NK) cells. Both of these cell types possess receptors that can recognize and interact with HLA molecules. Typically, T cells expressing the CD4 molecule recognize HLA class II molecules, and T cells expressing CD8 recognize HLA class I molecules. The specificity of interaction is determined during development of T cells within the thymus, such that circulating T cells should not interact with HLA molecules presenting peptides derived from normally expressed self proteins. However, the presentation of non-self peptides, for example peptides derived from viral or bacterial proteins, or aberrant expression of tumour antigens, can initiate activatory signals mediated by the T-cell receptor, resulting in the generation of an immune response against infected cells.

The interactions between HLA molecules and NK cell receptors play an important role in the function of NK cells. NK cells primarily function in innate immune responses. These cells express a range of receptors that can elicit either activatory or inhibitory signals. It is the balance between the two opposing signals that determines the action of an NK cell. Typically, interaction between HLA molecule and corresponding NK receptor resulting in a negative signal will outweigh any activatory signals; thus, the NK cell will not attack the cell expressing the HLA molecule. However, if a cell has lost expression of HLA molecules such as after malignancy or virus-induced downregu-lation, then the absence of the inhibitory signal will result in the activatory signal being dominant and allow NK cell-mediated attack on the target cell.

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